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Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity

Nature Medicine volume 20, pages 911–918 (2014)Cite this article

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Abstract

Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet–induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.

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Figure 1: Browning phenotype of WAT in Notch-signaling mutant mice.
Figure 2: Improved glucose metabolism in Notch-signaling mutant mice.
Figure 3: Resistance of aNotch1 mice to HFD-induced obesity.
Figure 4: Activation of Notch1 in adipocytes inhibits browning and glucose metabolism.
Figure 5: Notch signaling inhibits the expression of Ppargc1a and Prdm16 in cultured white adipocytes.
Figure 6: Inhibition of Notch in Lep-deficient obese mice (Lepob) ameliorates obesity and glucose metabolism.

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Acknowledgements

We thank T. Honjo (Kyoto University, Japan) for providing the Rbpjflox/flox mice; Dow AgroScience for providing Methocel E4M reagent; K. Ajuwon for providing access to the calorimetry facility; S. Koser and S. Donkin for assistance with luciferase assays; D. Zhou for Odyssey imaging facility support; T. Wiegand and C. Bain for assistance with histology; J. Wu and S. Hobaugh for maintaining mouse colonies; and members of the Kuang laboratory for comments. This work was partially supported by a grant from the US National Institutes of Health (R01AR060652 to S.K.).

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Authors and Affiliations

  1. Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA

    Pengpeng Bi, Tizhong Shan, Weiyi Liu, Feng Yue, Xin Yang, Xin-Rong Liang, Jinghua Wang & Shihuan Kuang

  2. Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA

    Jie Li & Xiaoqi Liu

  3. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Nadia Carlesso

  4. Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA

    Xiaoqi Liu & Shihuan Kuang

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Contributions

P.B. and S.K. conceived the project, designed the experiments and prepared the manuscript. P.B., T.S., W.L., F.Y., X.Y., X.-R.L., J.W. and J.L. performed the experiments. N.C. provided reagents. P.B., T.S., W.L., X.L. and S.K. analyzed the data.

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Correspondence to Shihuan Kuang.

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Supplementary Figures 1–7 and Supplementary Table 1 (PDF 823 kb)

Supplementary Video 1

Movement of WT (left) and aNotch1 (right) mice in the new cages. (MOV 3831 kb)

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Bi, P., Shan, T., Liu, W. et al. Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity. Nat Med 20, 911–918 (2014). https://doi.org/10.1038/nm.3615

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